Vitamin C to Decrease Effects of Smoking during Pregnancy on Offspring Airway Function, Airway Size, and Epigenetic Correlates: VCSIP cohort follow-up through 10 Years of Age

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Project Summary/Abstract Maternal smoking during pregnancy leads to impaired fetal lung development, decreased airway function (forced expiratory flows), and an increased risk for wheeze/asthma in the offspring. It is an important determinant of lifelong lower airway function and greater respiratory morbidity. In our randomized controlled trial (“Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function” [VCSIP]), we demonstrated that vitamin C supplementation versus placebo to pregnant smokers resulted in better airway function in the offspring at 3 and 12 months, and at 5 years of age. These differences in airway function between the offspring of the randomized groups also increased with age. We also demonstrated a significant decrease in the occurrence of wheeze at 4 to 6 years of age. There was no difference in prenatal or postnatal smoke exposure between the randomized groups. All clinical participants and investigators remain blinded to treatment allocations. Mediation analysis indicates the effect of vitamin C on wheeze is primarily due to its effect on airway function. Interventions early in life are important as longitudinal studies demonstrate that airway function trajectories are established early, and children in the lower airway function percentiles tend to have persistently lower airway function into adulthood and are likely at increased risk for adult pulmonary disease. Our studies are the first and only studies to show that an in-utero intervention targeted for a known environmental toxin can produce a persistent increase in airway function early in life. This finding is highly relevant to the aims of the NHLBI. The aims of this proposal are to continue to study the offspring from the unique VCSIP study to determine whether prenatal supplementation with vitamin C to pregnant smokers produces an improved trajectory of airway function and lower respiratory morbidity through 10 years of age (specific aim 1). In specific aims 2 and 3 we will examine the structural and molecular mechanisms by which vitamin C may be acting to modify the effects of maternal smoking during pregnancy on lung development. In specific aim 2, we will use low dose high-resolution computed tomography (HRCT) scans done at 10 years of age to determine if increased airway size underlies the improved airway function. In specific aim 3, evaluating DNA methylation changes in serial buccal and blood samples, we will identify critical genes and pathways most affected by maternal smoking during pregnancy and modified by vitamin C supplementation, as well as their association with respiratory outcomes of airway function, respiratory morbidity, and airway size. The children will be studied with yearly airway function tests, buccal swabs, hair for nicotine levels, blood at ages 7 and 10, and a low dose HRCT scan at 10 years of age. This follow-up will determine whether the vitamin C supplementation in pregnant smokers improves airway function and respiratory morbidity into mid-childhood, determine if the mechanism for the improved airway function is increased airway size, and explore the epigenetic changes that may underlie these beneficial effects of vitamin C supplementation for pregnant smokers.